BTRX-246040 ACTS THROUGH THE VENTROLATERAL PERIAQUEDUCTAL GRAY TO EXERT ANTIDEPRESSANT-RELEVANT ACTIONS IN MICE

Abstract Background BTRX-246040, a nociceptin/orphanin FQ peptide receptor antagonist, is being developed for the treatment of depressive patients[1,2]. However, the underlying mechanism of this potential antidepressant is still largely unclear. Here, we studied the antidepressant-related actions of BTRX- 246040 in the ventrolateral periaqueductal gray (vlPAG). Methods The tail suspension test, forced swim test, female urine sniffing test, sucrose preference test, and learned helplessness (LH) combined with pharmacological approaches were employed to examine the antidepressant-like effects and drug effects on LH-induced depressive-like behavior in C57BL/6J mice. Electrophysiological recordings in vlPAG neurons were used to study synaptic activity. Results Intraperitoneal administration of BTRX-246040 produced antidepressant-like behavioral effects in a dose dependent manner. Systemic BTRX-246040 (10 mg/kg) resulted in an increased frequency and amplitude of miniature excitatory postsynaptic currents (EPSCs) in the vlPAG. Moreover, slice perfusion of BTRX-246040 directly elevated the frequency and amplitude of miniature EPSCs and enhanced the evoked EPSCs in the vlPAG, which were blocked by pretreatment with the nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198. In addition, intra-vlPAG application of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Moreover, intra-vlPAG pretreatment with 6-cyano-7-nitroquinoxaline-2,3-dione reversed both systemic and local BTRX-246040– mediated antidepressant-like behavioral effects. Furthermore, both systemic and local BTRX-246040 decreased the LH phenotype and reduced LH-induced depressive-like behavior. Conclusions The results suggested that BTRX-246040 may act through the vlPAG to exert antidepressant-relevant actions. The present study provides new insight into a vlPAG-dependent mechanism underlying the antidepressant-like actions of BTRX-246040. References [1]Post, A., Smart, T., Krikke-Workel, J. et al. A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies. Neuropsychopharmacol 41, 1803–1812 (2016). [2]Witkin J.M., Wallace T.L., Martin W.J. Therapeutic approaches for NOP receptor antagonists in neurobehavioral disorders: clinical studies in major depressive disorder and alcohol use disorder with BTRX-246040 (LY2940094). Handb Exp Pharmacol 254, 399–415 (2019).